Theoretical Relationship Between Dose, Elimination Rate, and Duration of Pharmacologic Effect of Drugs

Levy, Gerhard; Nelson, Eino

doi:10.1002/jps.2600540540

Cited by 29 publications

(10 citation statements)

References 3 publications

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“…It has been pointed out that a linear relationship may be expected be tween the duration of a pharmacologic effect and the logarithm of an in jected or a relatively rapidly absorbed dose of a drug, provided that (a) the intensity of the effect at a given time is a function of the amount of drug in the body at that time, (b) drug metabolites are inactive or very rapidly eliminated, and (c) the drug is eliminated by apparent first-order kinetics with the rate constant being independent of dose (21,38,39). The slope of the line of a plot of duration of effect versus logarithm of dose is equal to 2.303jk and thereby permits an estimation of the elimination rate constant (k).…”

Section: Single Compartment Kineticsmentioning

confidence: 99%

Pharmacokinetics of Drug Action

Lévy¹,

Gibaldi²

1972

Annu. Rev. Pharmacol.

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This is a review of the literature since 1960 on the kinetics of reversible pharmacologic effects in intact animals including man. No claim is made that this is a complete survey. It is practically impossible to conduct an effective literature search on the pharmacokinetics of drug action, since ti tles of papers and index terms do not usually indicate that the investigations are concerned with the time course of pharmacologic effects in relation to dose or drug concentrations. The kinetics of drug absorption, distribution, and elimination are not included in this review. The literature in this field has been reviewed only recently (1) and this subject has been dealt with in a number of recently published books (2-4). This review will consist of four sections. These will summarize the literature on the relationship be tween drug concentration and pharmacologic effect, the kinetics of drug ac tion in cases where the body can be characterized as a single compartment, the kinetics of drug action when the body acts as a multi-compartment sys tem, and the kinetics of indirect pharmacologic effects. While there has been some theoretical work on these subjects before 1960, most of the ex perimental studies and the quantitative correlations between the time course of drug levels in the body and the time course of pharmacologic effects have been carried out since then. These investigations were made possible largely by the extensive progress in analytical and computational methodology as well as in the ability to quantitate certain pharmacologic effects in animals and man. DRUG CONCENTRATION AND PHARMACOLOGIC EFFECTThe concept of a direct and rapidly reversible pharmacologic effect im plies that a given intensity of effect is associated with a particular drug concentration at the site of action. Consequently, there is likely to be a cor responding relationship between the intensity of a pharmacologic effect and the post-distributive concentration of drug in plasma or serum. For exam ple, in studies of individual differences in the effect of drugs in relation to drug concentration in tissues of rats, it has been found that the duration of narcosis produced by a constant dose of pentobarbital sodium differed widely in different rats. However the concentrations of pentobarbital in the brain and serum of these rats upon awakening showed no such differences 85 6529 Annu. Rev. Pharmacol. 1972.12:85-98. Downloaded from www.annualreviews.org Access provided by University of Sussex on 08/19/15. For personal use only.Quick links to online content Further ANNUAL REVIEWS

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Section: Single Compartment Kineticsmentioning

confidence: 99%

Pharmacokinetics of Drug Action

Lévy¹,

Gibaldi²

1972

Annu. Rev. Pharmacol.

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“…The first-order rate constants for the decay of the response (formal elimination constants; Pliska, 1966) k were determined according to Levy & Nelson (1965) as k = 2-3(íogD-íogd)/(tD-td), where D and d are a larger and a smaller dose of the sample or standard and tD, td are the durations of the respective responses measured as the time from the onset of the response until the return of the conductivity to the base-line value. The ratio of the formal elimination constants for the sample and standard (here LVP), &s/&lvp> is the index of persistence, a dimensionless, dose-independent characteristic of the duration of the effect (Pliska, 1966).…”

Section: Methodsmentioning

confidence: 99%

EXCRETION OF ANTIDIURETIC ACTIVITY IN THE URINE OF CATS AND RATS AFTER ADMINISTRATION OF THE SYNTHETIC HORMONOGEN, Nα-Glycyl-Glycyl-Glycyl-[8-Lysine]-Vasopressin (TRIGLYCYLVASOPRESSIN)

Kyncl¹,

Rudinger²

1970

Journal of Endocrinology

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The rate of excretion of antidiuretic activity in the urine of anaesthetized, water-loaded cats and of rats with familial diabetes insipidus after injection of single doses of lysine vasopressin (LVP) and of the long-acting analogue N\g=a\-glycyl-glycyl-glycyl-[8-lysine]-vasopressin (triglycylvasopressin) has been studied by assays in water-loaded rats.The excreted antidiuretic material in all experiments resembled LVP and differed from triglycylvasopressin in the time course of the recorded response, the slope of the log dose\p=m-\response relationship, and the index of persistence. The total antidiuretic activity excreted was a fraction of that of the injected LVP but equalled or exceeded the assayable activity of the dose of triglycylvasopressin injected.It is concluded that the excreted antidiuretic activity is due to LVP and that the excreted hormone originates from the triglycylvasopressin by enzymic activation in vivo.

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“…His teachers at SUNY Buffalo, including Dr. Gary Levy and Dr. Milo Gibaldi in pharmacokinetics, Dr. Michael Schwartz in physical pharmacy and Dr. Howard Schaefer in Medicinal Chemistry, introduced him to very modern, at the time, pharmaceutical sciences, including pharmacokinetics, physical pharmacy, and medicinal chemistry. Gordon remembers a course in Pharmacy Calculations (Pharmacy “Math”) and the math symbols and methods of compounding pharmacy, taught by Professor Eino Nelson, an early leader in the science of physical pharmacy, biopharmaceutics, and pharmacokinetics . What surprised him in this course was that Professor Nelson supplemented the course with teaching calculus.…”

Section: The Early Years: Seneca Falls and Buffalo New Yorkmentioning

confidence: 99%